Method for treating pain in trigeminal neuralgia

ABSTRACT

The present invention is directed to the use of a class of peptide compounds for treating pain in trigeminal neuralgia.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Ser. No.60/578,062, filed Jun. 9, 2004 and EPO 04013635.0, filed Jun. 9, 2004.

The present invention is directed to the use of a class of peptidecompounds for treating pain in trigeminal neuralgia.

Certain peptides are known to exhibit central nervous system (CNS)activity and are useful in the treatment of epilepsy and other CNSdisorders. These peptides which are described in the U.S. Pat. No.5,378,729 have the Formula (Ia):

wherein

R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryllower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkylheterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R isunsubstituted or is substituted with at least one electron withdrawinggroup or electron donating group;

R₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl loweralkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower cycloalkyl,lower cycloalkyl lower alkyl, each unsubstituted or substituted with anelectron donating group or an electron withdrawing group; and

R₂ and R₃ are independently hydrogen, lower alkyl, lower alkenyl, loweralkynyl, aryl lower alkyl, aryl, heterocyclic, heterocyclic lower alkyl,lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl loweralkyl, or Z-Y wherein R₂ and R₃ may be unsubstituted or substituted withat least one electron withdrawing group or electron donating group;

Z is O, S, S(O)_(a), NR₄, PR₄ or a chemical bond;

Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, loweralkynyl, halo, heterocyclic, heterocyclic lower alkyl, and Y may beunsubstituted or substituted with an electron donating group or anelectron withdrawing group, provided that when Y is halo, Z is achemical bond, or

ZY taken together is NR₄NR₅R₇, NR₄OR₅, ONR₄R₇, OPR₄R₅, PR₄OR₅, SNR₄R₇,NR₄SR₇, SPR₄R₅ or PR₄SR₇, NR₄PR₅R₆ or PR₄NR₅R₇,

R₄, R₅ and R₆ are independently hydrogen, lower alkyl, aryl, aryl loweralkyl, lower alkenyl, or lower alkynyl, wherein R₄, R₅ and R₆ may beunsubstituted or substituted with an electron withdrawing group or anelectron donating group; and

R₇ is R₆ or COOR₈ or COR₈;

R₈ is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl oralkyl group may be unsubstituted or substituted with an electronwithdrawing group or an electron donating group; and

n is 1-4; and

a is 1-3.

U.S. Pat. No. 5,773,475 also discloses additional compounds useful fortreating CNS disorders. These compounds areN-benzyl-2-amino-3-methoxy-propionamide having the Formula (IIa):

wherein

Ar is aryl which is unsubstituted or substituted with halo; R₃ is loweralkoxy; and R₁ is methyl.

The patents U.S. Pat. No. 5,378,729 and U.S. Pat. No. 5,773,475 arehereby incorporated by reference. However, neither of these patentsdescribes the use of these compounds as specific analgesics for thetreatment of pain in trigeminal neuralgia.

WO 02/074297 relates to the use of a compound according to Formula (IIa)wherein Ar is phenyl which may be substituted by at least one halo, R₃is lower alkoxy containing 1-3 carbon atoms and R₁ is methyl for thepreparation of pharmaceutical compositions useful for the treatment ofallodynia related to peripheral neuropathic pain.

WO 02/074784 relates to the use of a compound having Formula (Ia) or/andFormula (IIa) showing antinociceptive properties for treating differenttypes and symptoms of acute and chronic pain, especially non neuropathicinflammatory pain, e.g. rheumatoid arthritic pain or/and secondaryinflammatory osteo-arthritic pain.

Pain is a subjective experience and the perception of pain is performedin particular parts of the Central Nervous System (CNS). Usually noxious(peripheral) stimuli are transmitted to the Central Nervous System (CNS)beforehand, but pain is not always associated with nociception. A broadvariety of different types of clinical pain exists, that are derivedfrom different underlying pathophysiological mechanisms and that willneed different treatment approaches.

The perception of pain may be characterized by three major types ofclinical pain:

-   -   acute pain    -   chronic pain    -   neuropathic pain

Acute clinical pain may result from inflammation or soft tissue injury,for instance. This type of pain is adaptive and has the biologicallyrelevant function of warning and enabling healing and repair of analready damaged body part to occur undisturbed. A protective function isachieved by making the injured/inflamed area and surrounding tissuehypersensitive to all stimuli so that contact with any external stimulusis avoided. The neuronal mechanisms underlying this type of clinicalpain are fairly well understood and pharmacological control of acuteclinical pain is available and effective by means of e.g. Non-SteroidalAnti-inflammatory Drugs (NSAIDs) up to opioids depending on type andextension of the sensation.

Chronic clinical pain appears as sustained sensory abnormalitiesresulting from an ongoing peripheral pathology such as cancer or chronicinflammation (e.g. arthritis) or it can be independent of the initiatingtriggers. The latter being maladaptive, offering no survival advantageand very often no effective treatment is available.

There are several causes of human neuropathy with considerablevariability in symptoms and neurological deficits. Painful neuropathiesare defined as neurological disorders characterised by persistence ofpain and hypersensitivity in a body region, of which the sensoryinnervation has been damaged, but damage to sensory nerves does notalways produce neuropathic pain, usually loss of sensation rather thanhypersensitivity or pain are observed.

Neuropathic pain can be classified as peripheral and central neuropathicpain. Peripheral neuropathic pain is caused by injury or infection ofperipheral sensory nerves, whereas central neuropathic pain is caused bydamage to the CNS or/and the spinal cord. Both peripheral and centralneuropathic pain can occur without obvious initial nerve damage.

Common analgesics like opioids and non-steroidal anti-inflammatory drugs(NSAIDs) improve only insufficiently chronic abnormal pain syndromes asperipheral and central neuropathic pain due to insufficient efficacy orlimiting side effects. In the search for alternative treatment regimesto produce satisfactory and sustained pain relief, corticosteroids,conduction blockade, glycerol, antidepressants, local anesthetics,gangliosides and electrostimulation have been tried, but mainlyanti-convulsants have been found useful against various types ofperipheral neuropathic pain conditions. A subset of patients withneuropathic pain responds to opioids. Carbamazepine is effective inreducing pain in patients with trigeminal neuralgia.

If general overactivity and unleaded low threshold activation of sensoryneurons is considered as one of the main syndroms of neuropathy andneuropathic pain sensation with a marked mechanoallodynia as the mostdisabling clinical sympton, selective inhibition of thispathophysiological event instead of general inhibition of high thresholdnoxious stimuli (by e.g. local anesthetics) of the normal sensorynociception provides clear advantages.

The mechanisms of trigeminal neuralgia are poorly understood. Currenttreatments use a variety of pharmacological, surgical, physical andpsychological approaches. However, the evidence for many of thetreatments is still limited. Mononeuropathies in general can be causedby any trauma or lesion or may even exist without a known cause, as isvery often the case with atypical facial pain.

The use of compounds of Formula (Ib) or/and Formula (IIb) for treatmentof pain in trigeminal neuralgia has not been reported. Thus, the presentinvention concerns the use of said compounds of Formulae (Ib) or/and(IIb) for the preparation of a pharmaceutical composition for theprevention, alleviation or/and treatment of trigeminal neuropathic painand other forms of mononeuropathies or atypical facial pain.

Surprisingly, application of compounds (Ib) or/and (IIb), particularly(R)-2-acetamide-N-benzyl-3-methoxypropionamide (SPM 927) exhibited asignificant efficacy in reducing mechanical hypersensitivity in ratswith infraorbital nerve injury. Thus, the compounds are useful asanalgesic or/and anti-allodynic compounds for treating trigeminalneuropathic pain. Treatment with SPM 927 particularly leads to asignificant increase in the response threshold indicating analgesicor/and anti-allodynic activity in trigeminal neuralgia.

A compound according to the invention has the general Formula (Ib)

wherein

R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryllower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkylheterocyclic, lower cycloalkyl or lower cycloalkyl lower alkyl, and R isunsubstituted or is substituted with at least one electron withdrawinggroup, and/or at least one electron donating group;

R₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl loweralkyl, aryl, heterocyclic lower alkyl, lower alkyl heterocyclic,heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, eachunsubstituted or substituted with at least one electron donating groupand/or at least one electron withdrawing group;

and

R₂ and R₃ are independently hydrogen, lower alkyl, lower alkenyl, loweralkynyl, aryl lower alkyl, aryl, halo, heterocyclic, heterocyclic loweralkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyllower alkyl, or Z-Y wherein R₂ and R₃ may be unsubstituted orsubstituted with at least one electron withdrawing group and/or at leastone electron donating group;

Z is O, S, S(O)_(a), NR₄, NR′₆, PR₄ or a chemical bond;

Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, loweralkynyl, halo, heterocyclic, heterocyclic lower alkyl, lower alkylheterocyclic and Y may be unsubstituted or substituted with at least oneelectron donating group and/or at least one electron withdrawing group,provided that when Y is halo, Z is a chemical bond, or

ZY taken together is NR₄NR₅R₇, NR₄OR₅, ONR₄R₇, OPR₄R₅, PR₄OR₅, SNR₄R₇,NR₄SR₇, SP₄R₅, PR₄SR₇, NR₄PR₅R₆, PR₄NR₅R₇ or N⁺R₅R₆R₇,

R′₆ is hydrogen, lower alkyl, lower alkenyl, or lower alkenyl which maybe unsubstituted or substituted with at least one electron withdrawinggroup or/and at least one electron donating group;

R₄, R₅ and R₆ are independently hydrogen, lower alkyl, aryl, aryl loweralkyl, lower alkenyl, or lower alkynyl, wherein R₄, R₅ and R₆ mayindependently be unsubstituted or substituted with at least one electronwithdrawing group or/and at least one electron donating group;

R₇ is R₆ or COOR₈ or COR₈, which R₇ may be unsubstituted or substitutedwith at least one electron withdrawing group or/and at least oneelectron donating group;

R₈ is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl oralkyl group may be unsubstituted or substituted with at least oneelectron withdrawing group or/and at least one electron donating group;and

n is 1-4; and

a is 1-3.

Preferably the compound according has the general Formula (IIb)

wherein

Ar is aryl, especially phenyl, which is unsubstituted or substitutedwith at least one halo; R₃ is —CH₂-Q, wherein Q is lower alkoxy; and R₁is lower alkyl, especially methyl.

The present invention is also directed to a pharmaceutical compositioncomprising a compound according to Formula (Ib) or/and Formula (IIb)useful for the prevention, alleviation or/and treatment of trigeminalneuropathic pain.

The “lower alkyl” groups when used alone or in combination with othergroups, are lower alkyl containing from 1 to 6 carbon atoms, especially1 to 3 carbon atoms, and may be straight chain or branched. These groupsinclude methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiarybutyl, amyl, hexyl, and the like.

The “lower alkoxy” groups are lower alkoxy containing from 1 to 6 carbonatoms, especially 1 to 3 carbon atoms, and may be straight chain orbranched. These groups include methoxy, ethoxy, propoxy, butoxy,isobutoxy, tert-butoxy, pentoxy, hexoxy and the like.

The “aryl lower alkyl” groups include, for example, benzyl, phenylethyl,phenylpropyl, phenylisopropyl, phenylbutyl, diphenylmethyl,1,1-diphenylethyl, 1,2-diphenylethyl, and the like.

The term “aryl”, when used alone or in combination, refers to anaromatic group which contains from 6 up to 18 ring carbon atoms and upto a total of 25 carbon atoms and includes the polynuclear aromatics.These aryl groups may be monocyclic, bicyclic, tricyclic or polycyclicand are fused rings. A polynuclear aromatic compound as used herein, ismeant to encompass bicyclic and tricyclic fused aromatic ring systemscontaining from 10-18 ring carbon atoms and up to a total of 25 carbonatoms. The aryl group includes phenyl, and the polynuclear aromaticse.g., naphthyl, anthracenyl, phenanthrenyl, azulenyl and the like. Thearyl group also includes groups like ferrocenyl. Aryl groups may beunsubstituted or mono or polysubstituted with electron withdrawingor/and electron donating groups as described below.

“Lower alkenyl” is an alkenyl group containing from 2 to 6 carbon atomsand at least one double bond. These groups may be straight chained orbranched and may be in the Z or E form. Such groups include vinyl,propenyl, 1-butenyl, isobutenyl, 2-butenyl, 1-pentenyl, (Z)-2-pentenyl,(E)-2-pentenyl, (Z)-4-methyl-2-pentenyl, (E)-4-methyl-2-pentenyl,pentadienyl, e.g., 1, 3 or 2,4-pentadienyl, and the like.

The term “lower alkynyl” is an alkynyl group containing 2 to 6 carbonatoms and may be straight chained as well as branched. It includes suchgroups as ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl,2-pentynyl, 3-methyl-1-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl and the like.

The term “lower cycloalkyl” when used alone or in combination is acycloalkyl group containing from 3 to 18 ring carbon atoms and up to atotal of 25 carbon atoms. The cycloalkyl groups may be monocyclic,bicyclic, tricyclic, or polycyclic and the rings are fused. Thecycloalkyl may be completely saturated or partially saturated. Examplesinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl, cyclooctenyl,cycloheptenyl, decalinyl, hydroindanyl, indanyl, fenchyl, pinenyl,adamantyl, and the like. Cycloalkyl includes the cis or trans forms.Cycloalkyl groups may be unsubstituted or mono or polysubstituted withelectron withdrawing or/and electron donating groups as described below.Furthermore, the substituents may either be in endo or exo positions inthe bridged bicyclic systems.

The term “electron-withdrawing and electron donating” refer to theability of a substituent to withdraw or donate electrons, respectively,relative to that of hydrogen if the hydrogen atom occupied the sameposition in the molecule. These terms are well understood by one skilledin the art and are discussed in Advanced Organic Chemistry, by J. March,John Wiley and Sons, New York, N.Y., pp. 16-18(1985) and the discussiontherein is incorporated herein by reference. Electron withdrawing groupsinclude halo, including bromo, fluoro, chloro, iodo and the like; nitro,carboxy, lower alkenyl, lower alkynyl, formyl, carboxyamido, aryl,quaternary ammonium, haloalkyl such as trifluoromethyl, aryl loweralkanoyl, carbalkoxy and the like. Electron donating groups include suchgroups as hydroxy, lower alkoxy, including methoxy, ethoxy and the like;lower alkyl, such as methyl, ethyl, and the like; amino, loweralkylamino, di(loweralkyl) amino, aryloxy such as phenoxy, mercapto,lower alkylthio, lower alkylmercapto, disulfide (lower alkyldithio) andthe like. One of ordinary skill in the art will appreciate that some ofthe aforesaid substituents may be considered to be electron donating orelectron withdrawing under different chemical conditions. Moreover, thepresent invention contemplates any combination of substituents selectedfrom the above-identified groups.

The term “halo” includes fluoro, chloro, bromo, iodo and the like.

The term “acyl” includes lower alkanoyl containing from 1 to 6 carbonatoms and may be straight chains or branched. These groups include, forexample, formyl, acetyl, propionyl, butyryl, isobutyryl, tertiarybutyryl, pentanoyl and hexanoyl.

As employed herein, a heterocyclic group contains at least one sulfur,nitrogen or oxygen ring atom, but also may include several of said atomsin the ring. The heterocyclic groups contemplated by the presentinvention include heteroaromatics and saturated and partially saturatedheterocyclic compounds. These heterocyclics may be monocyclic, bicyclic,tricyclic or polycyclic and are fused rings. They may preferably containup to 18 ring atoms and up to a total of 17 ring carbon atoms and atotal of up to 25 carbon atoms. The heterocyclics are also intended toinclude the so-called benzoheterocyclics. Representative heterocyclicsinclude furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl,indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl,pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl,benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl,pyranyl, indazolyl, purinyl, indolinyl, pyrazolindinyl, imidazolinyl,imadazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl,pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino,oxetanyl, azetidinyl, the N-oxides of the nitrogen containingheterocycles, such as the N-oxides of pyridyl, pyrazinyl, andpyrimidinyl and the like. Heterocyclic groups may be unsubstituted ormono or polysubstituted with electron withdrawing or/and electrondonating groups.

The preferred heterocyclics are thienyl, furyl, pyrrolyl, benzofuryl,benzothienyl, indolyl, methylpyrrolyl, morpholinyl, pyridiyl, pyrazinyl,imidazolyl, pyrimidinyl, or pyridazinyl. The preferred heterocyclic is a5 or 6-membered heterocyclic compound. The especially preferredheterocyclic is furyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl, orpyridazinyl. The most preferred heterocyclics are furyl and pyridyl.

The preferred compounds are those wherein n is 1, but di (n=2), tri(n=3) and tetrapeptides (n=4) are also contemplated to be within thescope of the invention.

The preferred values of R is aryl lower alkyl, especially benzyl,especially those wherein the phenyl ring thereof is unsubstituted orsubstituted with electron donating groups or/and electron withdrawinggroups, such as halo (e.g., F).

The preferred R₁ is H or lower alkyl. The most preferred R₁ group ismethyl.

The preferred electron donating substituents or/and electron withdrawingsubstituents are halo, nitro, alkanoyl, formyl, arylalkanoyl, aryloyl,carboxyl, carbalkoxy, carboxamido, cyano, sulfonyl, sulfoxide,heterocyclic, guanidine, quaternary ammonium, lower alkenyl, loweralkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino,lower alkylamino, di(loweralkyl) amino, amino lower alkyl, mercapto,mercaptoalkyl, alkylthio, and alkyldithio. The term “sulfide”encompasses mercapto, mercapto alkyl and alkylthio, while the termdisulfide encompasses alkyldithio. Especially preferred electrondonating or/and electron withdrawing groups are halo or lower alkoxy,most preferred are fluoro or methoxy. These preferred substituents maybe present on any one of the groups in Formula (Ib) or/and (IIb), e.g.R, R₁, R₂, R₃, R₄, R₅, R₆, R′₆, R₇, R₈ and/or R₅₀ as defined herein.

The ZY groups representative of R₂ and R₃ include hydroxy, alkoxy, suchas methoxy, ethoxy, aryloxy, such as phenoxy; thioalkoxy, such asthiomethoxy, thioethoxy; thioaryloxy such as thiophenoxy; amino;alkylamino, such as methylamino, ethylamino; arylamino, such as anilino;lower dialkylamino, such as, dimethylamino; trialkyl ammonium salt,hydrazino; alkylhydrazino and arylhydrazino, such as N-methylhydrazino,N-phenylhydrazino, carbalkoxy hydrazino, aralkoxycarbonyl hydrazino,aryloxycarbonyl hydrazino, hydroxylamino, such as N-hydroxylamino(—NH—OH), lower alkoxy amino [(NHOR₁₈) wherein R₁₈ is lower alkyl],N-lower alkylhydroxylamino [(NR₁₈)OH wherein R₁₈ is lower alkyl],N-lower alkyl-O-lower alkylhydroxyamino, i.e., [N(R₁₈)OR₁₉ wherein R₁₈and R₁₉ are independently lower alkyl], and o-hydroxylamino (—O—NH₂);alkylamido such as acetamido; trifluoroacetamido; lower alkoxyamino,(e.g., NH(OCH₃); and heterocyclicamino, such as pyrazoylamino.

The preferred heterocyclic groups representative of R₂ and R₃ aremonocyclic 5- or 6-membered heterocyclic moieties of the formula:

or those corresponding partially or fully saturated form thereof whereinn is 0 or 1; and

R₅₀ is H or an electron withdrawing group or electron donating group;

A, E, L, J and G are independently CH, or a heteroatom selected from thegroup consisting of N, O, S;

but when n is 0, G is CH, or a heteroatom selected from the groupconsisting of NH, O and S with the proviso that at most two of A, E, L,J and G are heteroatoms.

When n is 0, the above heteroaromatic moiety is a five membered ring,while if n is 1, the heterocyclic moiety is a six membered monocyclicheterocyclic moiety. The preferred heterocyclic moieties are thoseaforementioned heterocyclics which are monocyclic.

If the ring depicted hereinabove contains a nitrogen ring atom, then theN-oxide forms are also contemplated to be within the scope of theinvention.

When R₂ or R₃ is a heterocyclic of the above formula, it may be bondedto the main chain by a ring carbon atom. When n is 0, R₂ or R₃ mayadditionally be bonded to the main chain by a nitrogen ring atom.

Other preferred moieties of R₂ and R₃ are hydrogen, aryl, e.g., phenyl,aryl alkyl, e.g., benzyl and alkyl.

It is to be understood that the preferred groups of R₂ and R₃ may beunsubstituted or mono or poly substituted with electron donating or/andelectron withdrawing groups. It is preferred that R₂ and R₃ areindependently hydrogen, lower alkyl, which is either unsubstituted orsubstituted with electron withdrawing groups or/and electron donatinggroups, such as lower alkoxy (e.g., methoxy, ethoxy, and the like),N-hydroxylamino, N-lower alkylhydroxyamino, N-loweralkyl-O-loweralkyland alkylhydroxyamino.

It is preferred that one of R₂ and R₃ is hydrogen.

It is preferred that n is one.

It is more prefered that n=1 and one of R₂ and R₃ is hydrogen. It isespecially preferred that in this embodiment, R₂ is hydrogen and R₃ islower alkyl or ZY;

Z is O, NR₄ or PR₄; Y is hydrogen or lower alkyl; ZY is

In another especially preferred embodiment, n=1, R₂ is hydrogen and R₃is lower alkyl which may be substituted or unsubstituted with anelectron donating or electron withdrawing group, NR₄OR₅, or ONR₄R₇.

In yet another especially preferred embodiment, n=1, R₂ is hydrogen andR₃ is lower alkyl which is unsubstituted or substituted with hydroxy orloweralkoxy, NR₄OR₅ or ONR₄R₇, wherein R₄, R₅ and R₇ are independentlyhydrogen or lower alkyl, R is aryl lower alkyl, which aryl group may beunsubstituted or substituted with an electron withdrawing group and R₁is lower alkyl. In this embodiment it is most preferred that aryl isphenyl, which is unsubstituted or substituted with halo.

It is preferred that R₂ is hydrogen and R₃ is hydrogen, an alkyl groupwhich is unsubstituted or substituted by at least an electron donatingor electron withdrawing group or ZY. In this preferred embodiment, it ismore preferred that R₃ is hydrogen, an alkyl group such as methyl, whichis unsubstituted or substituted by an electron donating group, or NR₄OR₅or ONR₄R₇, wherein R₄, R₅ and R₇ are independently hydrogen or loweralkyl. It is preferred that the electron donating group is lower alkoxy,and especially methoxy or ethoxy.

It is preferred that R₂ and R₃ are independently hydrogen, lower alkyl,or ZY;

Z is O, NR₄ or PR₄;

Y is hydrogen or lower alkyl or

It is also preferred that R is aryl lower alkyl. The most preferred arylfor R is phenyl. The most preferred R group is benzyl. In a preferredembodiment, the aryl group may be unsubstituted or substituted with anelectron donating or electron withdrawing group. If the aryl ring in Ris substituted, it is most preferred that it is substituted with anelectron withdrawing group, especially on the aryl ring. The mostpreferred electron withdrawing group for R is halo, especially fluoro.

The preferred R₁ is lower alkyl, especially methyl.

It is more preferred that R is aryl lower alkyl and R₁ is lower alkyl.

Further preferred compounds are compounds of Formula (Ib) wherein n is1; R₂ is hydrogen; R₃ is hydrogen, a lower alkyl group, especiallymethyl which is substituted by an electron donating or electronwithdrawing group or ZY; R is aryl, aryl lower alkyl, such as benzyl,wherein the aryl group is unsubstituted or substituted with an electrondonating or electron withdrawing group and R₁ is lower alkyl. In thisembodiment, it is more preferred that R₃ is hydrogen, a lower alkylgroup, especially methyl, which may be substituted by electron donatinggroup, such as lower alkoxy, (e.g., methoxy, ethoxy and the like),NR₄OR₅ or ONR₄R₇ wherein these groups are defined hereinabove.

The most preferred compounds utilized are those of the Formula (IIb):

wherein

Ar is aryl, especially phenyl, which is unsubstituted or substitutedwith at least one electron donating group or electron withdrawing group,especially halo,

R₁ is lower alkyl, especially containing 1-3 carbon atoms; and

R₃ is as defined herein, but especially hydrogen, loweralkyl, which isunsubstituted or substituted by at least an electron donating group orelectron withdrawing group or ZY. It is even more preferred that R₃ is,in this embodiment, hydrogen, an alkyl group which is unsubstituted orsubstituted by an electron donating group, NR₄OR₅ or ONR₄R₇. It is mostpreferred that R₃ is CH₂-Q, wherein Q is lower alkoxy, especiallycontaining 1-3 carbon atoms; NR₄OR₅ or ONR₄R₇ wherein R₄ is hydrogen oralkyl containing 1-3 carbon atoms, R₅ is hydrogen or alkyl containing1-3 carbon atoms, and R₇ is hydrogen or alkyl containing 1-3 carbonatoms.

The most preferred R₁ is CH₃. The most preferred R₃ is CH₂-Q, wherein Qis methoxy.

The most preferred aryl is phenyl. The most preferred halo is fluoro.

The most preferred compounds include:

-   (R)-2-acetamido-N-benzyl-3-methoxy-propionamide;-   O-methyl-N-acetyl-D-serine-m-fluorobenzyl-amide;-   O-methyl-N-acetyl-D-serine-p-fluorobenzyl-amide;-   N-acetyl-D-phenylglycine benzylamide;-   D-1,2-(N,O-dimethylhydroxylamino)-2-acetamide acetic acid    benzylamide;-   D-1,2-(O-methylhydroxylamino)-2-acetamido acetic acid benzylamide.

It is to be understood that the various combinations and permutations ofthe Markush groups of R₁, R₂, R₃, R and n described herein arecontemplated to be within the scope of the present invention. Moreover,the present invention also encompasses compounds and compositions whichcontain one or more elements of each of the Markush groupings in R₁, R₂,R₃, n and R and the various combinations thereof. Thus, for example, thepresent invention contemplates that R₁ may be one or more of thesubstituents listed hereinabove in combination with any and all of thesubstituents of R₂, R₃, and R with respect to each value of n.

The compounds utilized in the present invention may contain one or moreasymmetric carbons and may exist in racemic and optically active forms.The configuration around each asymmetric carbon can be either the D or Lform. It is well known in the art that the configuration around a chiralcarbon atoms can also be described as R or S in the Cahn-Prelog-lngoldnomenclature system. All of the various configurations around eachasymmetric carbon, including the various enantiomers and diastereomersas well as racemic mixtures and mixtures of enantiomers, diastereomersor both are contemplated by the present invention.

In the principal chain, there exists asymmetry at the carbon atom towhich the groups R₂ and R₃ are attached. When n is 1, the compounds ofthe present invention is of the formula

wherein R, R₁, R₂, R₃, R₄, R₅, R₆, R′₆, R₇, R₈, R₅₀ Z and Y are asdefined previously.

As used herein, the term configuration shall refer to the configurationaround the carbon atom to which R₂ and R₃ are attached, even thoughother chiral centers may be present in the molecule. Therefore, whenreferring to a particular configuration, such as D or L, it is to beunderstood to mean the D or L stereoisomer at the carbon atom to whichR₂ and R₃ are attached. However, it also includes all possibleenantiomers and diastereomers at other chiral centers, if any, presentin the compound.

The compounds of the present invention are directed to all the opticalisomers, i.e., the compounds of the present invention are either theL-stereoisomer or the D-stereoisomer (at the carbon atom to which R₂ andR₃ are attached). These stereoisomers may be found in mixtures of the Land D stereoisomer, e.g., racemic mixtures. The D stereoisomer ispreferred.

More preferred is a compound of Formula (III) in the R configuration,preferably substantially enantiopure, wherein the substituent R isbenzyl which is unsubstituted or substituted with at least one halogroup, wherein R₃ is CH₂-Q, wherein Q is lower alkoxy containing 1-3carbon atoms and wherein R₁ is methyl. Preferably R is unsubstitutedbenzyl or benzyl substituted with at least one halo group which is afluoro group.

Depending upon the substituents, the present compounds may form additionsalts as well. All of these forms are contemplated to be within thescope of this invention including mixtures of the stereoisomeric forms.

The manufacture of the utilized compounds is described in U.S. Pat. Nos.5,378,729 and 5,773,475, the contents of both of which are incorporatedby reference.

The compounds utilized in the present invention are useful as such asdepicted in the Formulae (Ib) or/and (IIb) or can be employed in theform of salts in view of its basic nature by the presence of the freeamino group. Thus, the compounds of Formulae (Ib) or/and (IIb) formsalts with a wide variety of acids, inorganic and organic, includingpharmaceutically acceptable acids. The salts with therapeuticallyacceptable acids are of course useful in the preparation of formulationwhere enhanced water solubility is most advantageous.

These pharmaceutically acceptable salts have also therapeutic efficacy.These salts include salts of inorganic acids such as hydrochloric,hydroiodic, hydrobromic, phosphoric, metaphosphoric, nitric acid andsulfuric acids as well as salts of organic acids, such as tartaric,acetic, citric, malic, benzoic, perchloric, glycolic, gluconic,succinic, aryl sulfonic, (e.g., p-toluene sulfonic acids,benzenesulfonic), phosphoric, malonic, and the like.

The present invention is further directed to a method for theprevention, alleviation or/and treatment of a disease or condition asdescribed above in a mammal, including a human being, comprisingadministering at least one compound of Formulae (Ib) or/and (IIb).

It is preferred that the compound utilized in the present invention isused in therapeutically effective amounts.

The physician will determine the dosage of the present therapeuticagents which will be most suitable and it will vary with the form ofadministration and the particular compound chosen, and furthermore, itwill vary with the patient under treatment, the age of the patient, thetype of malady being treated. He will generally wish to initiatetreatment with small dosages substantially less than the optimum dose ofthe compound and increase the dosage by small increments until theoptimum effect under the circumstances is reached. When the compositionis administered orally, larger quantities of the active agent will berequired to produce the same effect as a smaller quantity givenparenterally. The compounds are useful in the same manner as comparabletherapeutic agents and the dosage level is of the same order ofmagnitude as is generally employed with these other therapeutic agents.

In a preferred embodiment, the compounds of the present invention areadministered in amounts ranging from about 1 mg to about 100 mg perkilogram of body weight per day, more preferably in amounts ranging fromabout 1 mg to about 10 mg per kilogram of body weight per day. Thisdosage regimen may be adjusted by the physician to provide the optimumtherapeutic response. Patients in need thereof may be treated with dosesof the compound of the present invention of at least 50 mg/day,preferably of at least 200 mg/day, more preferably of at least 300mg/day and most preferably of at least 400 mg/day. For example, apatient in need thereof may be treated with doses at a maximum of 6g/day, more preferably a maximum of 1 g/day and most preferably amaximum of 600 mg/day. In some cases, however, lower or higher doses maybe needed.

In another preferred embodiment, the daily doses are increased until apredetermined daily dose is reached which is maintained during thefurther treatment.

In yet another preferred embodiment, several divided doses may beadministered daily. For example, three doses per day may beadministered, preferably two doses per day. It is more preferred toadminister a single dose per day.

In yet another preferred embodiment, an amount of the compounds of thepresent invention may be administered which results in a plasmaconcentration of 0.1 to 15 μg/ml (trough) and 5 to 18.5 μg/ml (peak),calculated as an average over a plurality of treated subjects.

The compounds of Formulae (Ib) or/and (IIb) may be administered in aconvenient manner, such as by oral, intravenous (where water soluble),intramuscular, intrathecal or subcutaneous routes. Oral or/and i.v.administration is preferred.

The pharmaceutical composition of the present invention may be preparedfor the treatment regimen as described above, in particular for thetreatment with doses as described above, to effect plasma concentrationsas described above, for administration periods or/and administrationroutes as specified in the embodiments of the present invention asdescribed above.

In another preferred embodiment, the method of the present invention asdescribed above for the treatment of a mammal including a human being inneed thereof comprises administering a compound of the present inventionin combination with administering a further active agent for theprevention, alleviation or/and treatment of trigeminal neuropathic pain.The compound of the present invention and the further active agent maybe administered together, i.e. in a single dose form, or may beadministered separately, i.e. in a separate dose form. Thus, thepharmaceutical composition of the present invention may comprise acompound of the present invention as defined above and may furthercomprise a further active agent for the prevention, alleviation or/andtreatment of trigeminal neuropathic pain. The pharmaceutical compositionmay comprise a single dose form or may comprise a separate dose formcomprising a first composition comprising a compound of the presentinvention as defined above and a second composition comprising thefurther active agent.

The compounds of the present invention may be used for the preparationof a pharmaceutical composition as described above.

The compounds of Formulae (Ib) or/and (IIb) may be orally administered,for example, with an inert diluent or with an assimilable ediblecarrier, or it may be enclosed in hard or soft shell gelatin capsules,or it may be compressed into tablets, or it may be incorporated directlyinto the fool of the diet. For oral therapeutic administration, theactive compound of Formulae (Ib) or/and (IIb) may be incorporated withexcipients and used in the form of ingestible tablets, buccal tablets,troches, capsules, elixirs, suspensions, syrups, wafers, and the like.Such compositions and preparations should contain at least 1% of activecompound of Formulae (Ib) or/and (IIb). The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 5 to about 80% of the weight of the unit.The amount of active compound of Formulae (Ib) or/and (IIb) in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained. Preferred compositions or preparations according to thepresent invention contains between about 10 mg and 6 g active compoundof Formulae (Ib) or/and (IIb).

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier.

Various other materials may be present as coatings or otherwise modifythe physical form of the dosage unit. For instance, tablets, pills, orcapsules may be coated with shellac, sugar or both. A syrup or elixirmay contain the active compound, sucrose as a sweetening agent, methyland propylparabens as preservatives, a dye and flavoring such as cherryor orange flavor. Of course, any material used in preparing any dosageunit form should be pharmaceutically pure and substantially non-toxic inthe amounts employed. In addition, the active compound may beincorporated into sustained-release preparations and formulations. Forexample, sustained release dosage forms are contemplated wherein theactive ingredient is bound to an ion exchange resin which, optionally,can be coated with a diffusion barrier coating to modify the releaseproperties of the resin.

The active compound may also be administered parenterally orintraperitoneally. Dispersions can also be prepared in glycerol, liquid,polyethylene glycols, and mixtures thereof and in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersions. In all cases the form must be sterile and mustbe fluid to the extent that easy syringability exists. It must be stableunder the conditions of manufacture and storage and must be preservedagainst the contaminating action of microorganisms such as bacteria andfungi. The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetable oils. The proper fluidity can be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersions and by the use ofsurfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminiummonostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredient into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying the freeze-dryingtechnique plus any additional desired ingredient from previouslysterile-filtered solution thereof.

As used herein, “pharmaceutically acceptable carrier” includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagent, isotonic and absorption delaying agents for pharmaceutical activesubstances as well known in the art. Except insofar as any conventionalmedia or agent is incompatible with the active ingredient, its use inthe therapeutic compositions is contemplated. Supplementary activeingredients can also be incorporated into the compositions.

It is especially advantageous to formulate parenteral compositions indosage unit form or ease of administration and uniformity of dosage.Dosage unit form as used herein refers to physically discrete unitssuited as unitary dosages for the mammalian subjects to be treated; eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. The specifics for the novel dosage unitforms of the invention are dictated by and directly dependent on (a) theunique characteristics of the active material an the particulartherapeutic effect to be achieved, and (b) the limitations inherent inthe art of compounding such as active material for the treatment ofdisease in living subjects having a diseased condition in which bodilyhealth is impaired as herein disclosed in detail.

The principal active ingredient is compounded for convenient andeffective administration in effective amounts with a suitablepharmaceutically acceptable carrier in dosage unit form as hereinbeforedescribed. A unit dosage form can, for example, contain the principalactive compound in amounts ranging from about 10 mg to about 6 g.Expressed in proportions, the active compound is generally present infrom about 1 to about 750 mg/ml of carrier. In the case of compositionscontaining supplementary active ingredients, the dosages are determinedby reference to the usual dose and manner of administration of the saidingredients.

As used herein the term “patient” or “subject” refers to a warm bloodedanimal, and preferably mammals, such as, for example, cats, dogs,horses, cows, pigs, mice, rats and primates, including humans. Thepreferred patient is a human.

The term “treat” refers to either relieving the pain associated with adisease or condition or alleviating the patient's disease or condition.

The compounds of the present invention are administered to a patientsuffering from the aforementioned type of pain in an analgesic effectiveamount. These amounts are equivalent to the therapeutically effectiveamounts described hereinabove.

The following example shows the properties of SPM 927 in reducingtrigeminal pain in a rats with ischemic infraorbital nerve injury.

The used substance was SPM 927 which is the synonym for Harkoseride. Thestandard chemical nomenclature is(R)-2-acetamide-N-benzyl-3-methoxypropionamide.

FIGURE LEGEND

FIG. 1 shows the effect (median±median absolute deviation, M.A.D.) ofadministration of vehicle (n=23 males, open circles) or SPM 927 at 7.5mg/kg (open circles, 7 females), SPM 927 at 15 (open squares, 7 females,8 males), 20 (filled circles, 7 females, 7 males) and 30 mg/kg (filledsquares, 15 males) on vocalization threshold to stimulation with vonFrey hairs in male (A) and female (B) rats after infraorbital (IoN)nerve injury. *=p<0.05 and **=p<0.01 compared to baseline at time 0 withWilcoxon signed-ranks test.

EXAMPLE

The present study, shows the analgesic effects SPM 927 in a rat model ofinjury to the infraorbital nerve (IoN) which is regarded as a model oftrigeminal neuropathic pain.

Materials and Methods

Male and female Sprague-Dawley rats (Mölleg{dot over (a)}rd, Denmark)weighing 200-250 g at the start of the experiments were used. Allexperimental procedures were approved by the local research ethicscommittee.

Photochemically-Induced Ischemic Infraorbital Nerve (IoN) Injury

Rats were anesthetized with chloral hydrate. The left IoN was exposedvia a longitudinal incision at the maxillary region and all branches ofthe nerve were carefully lifted on a glass hook. A piece of aluminiumfoil was placed under the nerve and the nerve was irradiated for 6 minwith the tunable argon ion laser. The rat was positioned so that thelaser beam was perpendicular and transversal to the exposed nerve.Immediately before irradiation erythrosin B was injected i.v. and theinjection was repeated after 5 min. After irradiation the wound wasclosed in layers.

Assessment of Mechanical Sensitivity after IoN Injury

Mechanical sensitivity was tested with a series of von Frey filaments.The rat was gently held by the experimenter and the von Frey filamentswere applied in ascending order to the IoN territory on the hairy skinof the vibrissal pad. The stimulation with each filament consisted offour consecutive applications at 1/s on the injured and then on thecontralateral side. The response threshold was taken as the force atwhich the rat either exhibited a withdrawal reaction or escape/attack in75% of trials (Vos et al. 1994). The rats were habituated to the testingprocedure for several days before nerve injury and baseline response wasdetermined in two sessions. Testing was carried out 3, 7, 10 and 14 dafter the injury to assess the development of mechanicalhypersensitivity. The effect of SPM 927 (7.5, 15, 20 and 30 mg/kg) wastested 14-16 days after injury when mechanical hypersensitivity was wellestablished. Measurements were taken 30 min, 1 h, 2 h, and 3 h followingdrug injection.

Drugs and Statistics

SPM 927 was dissolved in physiological saline and injectedintraperitoneally. The data are expressed as median±M.A.D. and analysedwith Wilcoxon signed-ranks test.

Results

Effects of SPM 927 on Mechanical Hypersensitivity after IoN Injury

Partial injury to the IoN leads to the development of mechanicalhypersensitivity in the innervation area of the nerve. Normal responsethreshold to mechanical stimulation was between 18-40 g whereas afterinjury, the response threshold decreased significantly for both male andfemale rats (median 5.8 g and 4.0 g respectively). The mechanicalhypersensitivity developed rapidly after IoN nerve injury, reaching peaklevel within 3 days and was stable thereafter for at least 3-4 weekswith the irradiation parameter used in the present study. In male ratsSPM 927 at 15 or 20 mg/kg did not alleviate mechanical hypersensitivitywhereas at 30 mg/kg it significantly alleviated mechanicalhypersensitivity for 3 h (FIG. 1A). In female rats, SPM 927significantly and markedly alleviated mechanical hypersensitivity atdoses of 15 or 20 mg/kg whereas it has no effect at 7.5 mg/kg (FIG. 1B).SPM 927 did not cause motor deficits.

CONCLUSION

Systemic SPM 927 produced a dose-dependent analgesic or/andanti-allodynic effect in a rat model of trigeminal neuropathic painfollowing single dose administration. Thus, SPM 927 and relatedcompounds are useful for the treatment of pain during trigeminalneuralgia in mammals including humans. As this nerve injury can beregarded as a model for a mononeuropathy, SPM 927 and related compoundsare also useful for the treatment of pain resulting from neuropathies ofother nerves (mononeuropathies). Furthermore, it can be regarded as anextended model for atypical facial pain. Consequently, SPM 927 andrelated compounds are useful for the treatment of atypical facial pain.

REFERENCES

-   Vos, B. P., Strassmann, A. M. and Maciewicz R. J. Behavioral    evidence of trigeminal neuropathic pain following chronic    constriction injury to the rat's infraorbital nerve. J. Neurosci.    1994; 14:2708-2323.

1. A method for alleviating and/or treating neuropathic trigeminal painin a subject in need of such alleviation and/or treatment, the methodcomprising administering to a subject a compound of Formula (IIb)

wherein Ar is phenyl which is unsubstituted or substituted with at leastone halo group; R₃ is CH₂-Q, wherein Q is lower alkoxy containing 1-3carbon atoms; and R₁ is lower alkyl containing 1-3 carbon atoms, or apharmaceutically acceptable salt thereof, in a dosage amount of about 50mg/day to about 1 g/day.
 2. The method of claim 1, wherein the subjecthas neuropathic trigeminal pain and atypical facial pain.
 3. The methodof claim 1 wherein, in the compound of Formula (IIb), Ar isunsubstituted phenyl.
 4. The method of claim 1 wherein, in the compoundof Formula (IIb), halo is fluoro.
 5. The method of claim 1 wherein, inthe compound of Formula (IIb), R₃ is CH₂-Q, wherein Q is alkoxycontaining 1-3 carbon atoms, and Ar is unsubstituted phenyl.
 6. Themethod of claim 1, wherein the compound of Formula (IIb) is(R)-2-acetamido-N-benzyl-3-methoxypropionamide or a pharmaceuticallyacceptable salt thereof.
 7. The method of claim 6 wherein the compoundis substantially enantiopure.
 8. The method of claim 1, wherein thecompound is administered at increasing daily doses until a predetermineddaily dose is reached which is maintained during further treatment. 9.The method of claim 1, wherein the compound is administered in no morethan three doses per day.
 10. The method of claim 6, wherein thecompound is administered in an amount resulting in a plasmaconcentration of the compound of 0.1 to 15 μg/ml (trough) and 5 to 18.5μg/ml (peak).
 11. The method of claim 1, wherein the compound isadministered orally or intravenously.
 12. The method of claim 1, furthercomprising administering to the subject a further active agent foralleviation and/or treatment of neuropathic trigeminal pain.
 13. Themethod of claim 12, wherein the compound of Formula (IIb) and thefurther active agent are administered in a single dose.
 14. The methodof claim 1, wherein the subject is a mammal.
 15. The method of claim 14wherein the subject is a human.
 16. The method of claim 1, wherein thecompound of Formula (IIb) or a pharmaceutically acceptable salt thereofis administered in a dosage amount of about 200 mg/day to about 1 g/day.17. The method of claim 16, wherein the compound of Formula (IIb) or apharmaceutically acceptable salt thereof is administered in a dosageamount of about 200 mg/day to about 600 mg/day.
 18. The method of claim1, wherein the compound of Formula (IIb) is(R)-2-acetamido-N-benzyl-3-methoxypropionamide in an oral dosage amountof about 50 mg/day to about 600 mg/day.
 19. The method of claim 18,wherein the dosage amount is about 200 mg/day to about 600 mg/day.
 20. Amethod for alleviating and/or treating neuropathic trigeminal pain in asubject in need of such alleviation and/or treatment, the methodcomprising administering to the subject(R)-2-acetamido-N-benzyl-3-methoxypropionamide.